Targeting The Vicious Cycle Of Cancer-induced Bone Disease With TRAIL And Bisphosphonates
Funder
National Health and Medical Research Council
Funding Amount
$443,696.00
Summary
The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly ....The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly targeting cancer cells within bone, and with no evidence of toxic side effects to normal tissues. Death receptor targeting by TRAIL, and bisphosphonates induce cancer cell apoptosis through different but overlapping signaling pathways. Therefore, combination of the two approaches may facilitate killing of tumour cells that resist death induction through either one of the pathways. Combination therapy may also reduce the probability of acquired resistance to either therapy. We propose that a combinatorial approach, using bisphosphonates to selectively target osteoclasts and TRAIL to selectively target cancer cells, would be an ideal therapeutic and safe approach to delay, slow or completely eliminate growth of cancer within bone.Read moreRead less
A Solution Based Approach Developing Child Health Research With A Focus On Preventive Interventions For Common Childhood
Funder
National Health and Medical Research Council
Funding Amount
$2,599,538.00
Summary
There is an increasing recognition that research into child health should focus not only on disease but also on common childhood disorders such as obesity, depression and poor literacy. In addition, such research should include solution-based activity. That is, child health research should have an active program of testing new interventions to prevent the onset of disorders, or to allow optimal early management. The Murdoch Childrens Research Institute, the largest Australian child health resear ....There is an increasing recognition that research into child health should focus not only on disease but also on common childhood disorders such as obesity, depression and poor literacy. In addition, such research should include solution-based activity. That is, child health research should have an active program of testing new interventions to prevent the onset of disorders, or to allow optimal early management. The Murdoch Childrens Research Institute, the largest Australian child health research institute, is in a very good position to develop Australia's capacity further with regard to a coordinated research program into preventative interventions in child health. This is because of: - the Institute's location at the Royal Children's Hospital, Melbourne, the largest paediatric health service provider in Australia - the many individual relevant research projects that are already occurring in MCRI - the strong existing teams of researchers with skills in many different fields of child health such as psychology, speech pathology, clinical-medical care, epidemiology and biostatistics, and laboratory science including genetics. This capacity building program will coordinate population health work to develop the knowledge and skills of eight population health researchers. This development will occur within the context of an internationally competitive research program with structured continuing education and training to promote public health leadership. The capacity building program will develop skills not only in study design, conduct and analysis, but also in collaboration and the translation of research findings into better health services, government policy and parental knowledge to prevent problems and improve the health and well being of children and their families. To care for children in the best way, parents, families, schools, health care providers, and government need the best evidence base possible on the prevention of common child disorders.Read moreRead less
Analysis Of CD95L And TRAIL Apoptotic Pathways In Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$423,055.00
Summary
Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chem ....Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chemo- and radiotherapy, and therefore may have altered apoptotic pathways. By identifying the components of apoptotic pathways in glioma cells, rational design of either novel drugs, or treatments which will restore-enable susceptibility of the tumour cells to currently available therapies will be feasible. Here we will focus on the suicide pathways triggered by the molecules CD95L and TRAIL. We will characterise the sensitivity of glioma cells to CD95L and TRAIL, chemotherapeutic drugs and irradiation. We will then systematically survey the molecules implicated in CD95L and TRAIL-mediated cell death, based on studies in other cell types, to determine the relevant components of the molecular pathways which lead to apoptosis following CD95L-TRAIL exposure. We will also assess the roles played by known inhibitors, in determining resistance to CD95L and-or TRAIL, and will perform screens for novel inhibitors of these pathways. This study will elucidate the molecules responsible for the CD95L-TRAIL-mediated apoptosis seen in some glioma cells, and the molecules which confer resistance to these treatments in others. We will also learn whether the typical resistance to chemo- and radiotherapy observed in gliomas is mechanistically linked to resistance to CD95 and-or TRAIL resistance. This knowledge will be valuable for the rational design of diagnostic and therapeutic agents for glioma, and potentially for other diseases.Read moreRead less
Antitumour Efficacy Of TRAIL: An Immunotherapeutic Approach For The Treatment Of Skeletal Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$459,034.00
Summary
The most serious clinical problem with patients with solid tumours is metastasis to bone, which leads to complications that can cause erosion of the patient's quality of life, and eventually death. TRAIL is a new cancer therapeutic that selectively kills cancer cells while sparing normal cells. The use of TRAIL agonistic antibodies that do not bind OPG and have increased serum half life offers an exciting approach for the treatment of skeletal malignancies that is non toxic and safe.